Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 2C8 and/or 3A4 may decrease the plasma concentrations of dabrafenib, which is primarily metabolized by these isoenzymes. Administration of rifampin (600 mg once a day), a potent CYP450 3A4 and moderate CYP450 2C8 inducer, with dabrafenib (150 mg twice a day) for 10 days resulted in a decreased dabrafenib AUC (34%) and Cmax (27%). The AUC of the metabolite hydroxy-dabrafenib was not affected; however, the AUC increased by 73% for the metabolite carboxy-dabrafenib and decreased by 30% for desmethyl-dabrafenib.

MANAGEMENT: Concomitant use of dabrafenib with potent CYP450 2C8 or 3A4 inducers should generally be avoided. Otherwise, patients should be closely monitored for potential loss of efficacy of dabrafenib.

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of dabrafenib. In study subjects, administration of dabrafenib with a high-fat meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 51% and 31%, respectively, and delayed median Tmax by approximately 3.6 hours compared to administration in the fasted state.

MANAGEMENT: Dabrafenib should be taken at least 1 hour before or 2 hours after a meal.